Study on the Effect of a Beta Blocker on Increased Sensitivity to Pain in Humans Caused by Opioids

Phase 2

Completed

Conditions: Hyperalgesia

Interventions: Drug: Propranolol
Drug: Placebo to Match Propranolol
Drug: Remifentanil

Registration Number: NCT01222091

Lead Sponsor: Stanford University

Brief Summary: This research study explores whether a beta-blocker (propranolol) can prevent a person from becoming more sensitive to pain after administration of an opioid (remifentanil). Beta blockers inhibit the sympathetic (fight or flight) response and are often used to treat angina and high blood pressure. In a previous study in human volunteers, the investigators demonstrated an increased sensitivity to pain after a 60-minute infusion of the opioid remifentanil. The goal of this study is to identify a possible inhibitor of this phenomenon.

Detailed Description: Recent evidence suggests that opioid therapy may cause a biphasic response, i.e. initial pain relief followed paradoxically by a longer lasting hypersensitivity to pain. Recent genetic analysis in mice suggests that beta adrenergic receptor antagonists reduce opiate-induced hyperalgesia (OIH). The purpose of this study is to determine the analgesic and antihyperalgesic properties of the beta-blocker propranolol on remifentanil-induced hypersensitivity in humans.

The investigators want to determine the analgesic and antihyperalgesic properties of the beta-blocker propranolol on remifentanil-induced hypersensitivity in humans. The investigators hope to learn whether the administration of beta-blocker propranolol will significantly diminish the hyperalgesic response after administration of an opioid.

The primary outcome measure for this study is change in size (area) of secondary hyperalgesia after cessation of remifentanil infusion, a measure of OIH.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 10

Inclusion Criteria

Healthy men,
Age between 18 and 45 years
Normal weight (according to the table provided by Metropolitan Life Insurance).

Exclusion Criteria

Hypersensitivity to opioids or naloxone,
History of addictive disease,
Significant cardiac, respiratory, gastrointestinal, neurological, dermatological, and psychiatric diseases,
Concurrent medication with an analgesic drug,
Student and employees affiliated with our laboratory

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Propranolol, Then Placebo	Placebo to Match Propranolol	Propranolol, a beta blocker, or placebo to match, will be given to test whether or not it could modulate the expression of remifentanil-induced postinfusion hyperalgesia (RPH) during two pain test including: mechanically evoked pain to map the size of the hyperalgesic skin region caused by electrical stimulation and heat pain.
Placebo, Then Propranolol	Placebo to Match Propranolol	Propranolol, a beta blocker, or placebo to match, will be given to test whether or not it could modulate the expression of remifentanil-induced postinfusion hyperalgesia (RPH) during two pain test including: mechanically evoked pain to map the size of the hyperalgesic skin region caused by electrical stimulation and heat pain.
Propranolol, Then Placebo	Propranolol	Propranolol, a beta blocker, or placebo to match, will be given to test whether or not it could modulate the expression of remifentanil-induced postinfusion hyperalgesia (RPH) during two pain test including: mechanically evoked pain to map the size of the hyperalgesic skin region caused by electrical stimulation and heat pain.
Propranolol, Then Placebo	Remifentanil	Propranolol, a beta blocker, or placebo to match, will be given to test whether or not it could modulate the expression of remifentanil-induced postinfusion hyperalgesia (RPH) during two pain test including: mechanically evoked pain to map the size of the hyperalgesic skin region caused by electrical stimulation and heat pain.
Placebo, Then Propranolol	Propranolol	Propranolol, a beta blocker, or placebo to match, will be given to test whether or not it could modulate the expression of remifentanil-induced postinfusion hyperalgesia (RPH) during two pain test including: mechanically evoked pain to map the size of the hyperalgesic skin region caused by electrical stimulation and heat pain.
Placebo, Then Propranolol	Remifentanil	Propranolol, a beta blocker, or placebo to match, will be given to test whether or not it could modulate the expression of remifentanil-induced postinfusion hyperalgesia (RPH) during two pain test including: mechanically evoked pain to map the size of the hyperalgesic skin region caused by electrical stimulation and heat pain.

Primary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Size (Area) of Secondary Hyperalgesia After Cessation of Remifentanil Infusion, a Measure of Opioid-induced Hyperalgesia (OIH).	Baseline; 15 min post remifentanil (REM) infusion; 60 min post REM infusion	A slightly modified version of a previously described model of secondary hyperalgesia was used. Two copper wires contained in a microdialysis catheter were inserted in parallel over a length of 5 mm into the dermis of the right volar forearm. The wires were connected to a constant current stimulator controlled by a pulse generator to deliver rectangular and monophasic pulses with a duration of 0.5 mg at 2 Hz. Over a period of 15 min, the current was increased by targeting a pain rating of 5 on an 11-point numeric rating scale (0 = no pain and 10 = maximum tolerable pain) until the hyperalgesic area surrounding the stimulation site was fully established. Once the area was established, the current was held constant. Percent change from baseline in size (area) of secondary hyperalgesia after cessation of remifentanil infusion was calculated per group.

Secondary Outcome Measures

Name	Time	Method
Objective Opioid Withdrawal Scale (OOWS)	Pretreatment [90 min prior to 60-min REM infusion]; 30 min prior to 60-min REM infusion; 15 and 40 min after start of 60-min REM infusion; 5, 15, and 75 minutes after finish of 60-min REM infusion)	OOWS: Is a 13-item instrument of documenting physically observable signs of withdrawal, which are rated as present (1) or absent (0) during the observation period. Maximum score = 13, minimum score = 0. Lower scores correspond to fewer symptoms.